One crucial mechanism by which the skin defends the host against microbial infection involves the innate immune function of the epidermis, mediated in part by Langerhans cells (LC), a skin-specific resident dendritic cell (DC) subset, that instructs the adaptive T cell response. A unique aspect of LC is the co-expression of CD1a and the C-type lectin langerin. We demonstrated that LC contribute to the cutaneous immune response to Mycobacterium leprae (mLEP), the causative agent of leprosy via a langerin-dependent, CD1a-restricted antigen presentation pathway to T cells. We have uncovered new paradigms of CD1 immunobiology including: defining the structure of lipid-containing CD1-restricted T cell antigens, mechanisms of CD1 antigen presentation, mechanisms by which CD1 expression is regulated in skin, and the first evidence for a direct T cell mediated antimicrobial activity. Based on these findings, we are able to hypothesize a new paradigm for how LC and CD1a restricted T cells interact to recognize and control bacterial infections in the skin. Specifically: i) CD1a positive LC present bacterial lipoproteins antigens and that this presentation is linked to langerin mediated uptake of the pathogen or antigen; ii) antigen presentation by LC induces a novel cytotoxic T cell subset, the `polycytotoxic' T cell, that delivers the antimicrobial protein granulysin into infected target cells as part of a host defense response; and, iii) activated LC directly kill intracellular pathogens resulting in enhanced antige presentation to T cells. We propose studies to explore this new model of LC and CD1 immunobiology in relationship to host defense in skin through the study of leprosy as a model. We propose in Aim 1, determine the role of LC in the induction of `polycytotoxic' T cells in skin, in Aim 2, investigate the mechanisms by which CD1a-restricted T cells kill mLEP in LC, and, in Aim 3, elucidate the structure of antigens presented by LC via CD1a to T cells. These studies are intended to provide a comprehensive and in depth view of CD1-restricted T cell function and LC biology in relation to a model of human skin disease, leprosy, with the goal of understanding mechanisms of host defense to microbial pathogens in skin. Such insights could provide new avenues for development of immunomodulatory and immunoprophylactic treatments for a variety of human skin and infectious diseases.